Chemokines are chemotactic cytokines that are released by a wide variety of cells and attract various types of immune system cells, such as macrophages, T cells, eosinophils, basophils and neutrophils, to sites of inflammation (reviewed in Schall, Cytokine, 3:165-183 (1991), Schall, et al., Curr. Opin. Immunol., 6:865 873 (1994) and Murphy, Rev. Immun., 12:593-633 (1994)). In addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in responsive cells, including changes in cell shape, transient rises in the concentration of intracellular free calcium ions ([Ca2+]), granule exocytosis, integrin up-regulation, formation of bioactive lipids (e.g., leukotrienes) and respiratory burst, associated with leukocyte activation. Thus, the chemokines are early triggers of the inflammatory response, causing inflammatory mediator release, chemotaxis and extravasation to sites of infection or inflammation.
CCR9, a seven transmembrane, G-protein-coupled chemokine receptor was recently identified as the physiologic receptor for CCL25/thymus-expressed Chemokine (TECK). CCR9 is mainly expressed in thymocytes and T lymphocytes from the small intestine and colon. CCL25/TECK is predominantly expressed in the thymus and small intestine. Studies have shown that CCR9 mediates chemotaxis in response to CCL25/TECK and is likely to play an important role in regulating the trafficking of developing T cells within the thymus and be critical for the development, homeostasis, and/or function of mucosal T lymphocytes.
It has been shown that CCR9+ lymphocytes are markedly elevated in peripheral blood lymphocytes in patients with small bowel Crohn's or celiac disease. TECK expression is altered in an inflamed small bowel being intensely expressed in a patchy distribution in crypt epithelial cells in proximity to lymphocytic infiltrates (Papadakis et al. Gastroenterology, 2001, 121:246-254). In mouse models, neutralization of TECK inhibits homing of CD8+ T cells to the IEL (intraepithelial lymphocyte) compartment. This directly demonstrates that CCL25 and CCR9 function in recruiting effector lymphocytes to the small intestinal epithelium following their activation in gut-associated lymphoid tissue (GALT).
Targeting CCL25/TECK and/or CCR9 may provide a way to selectively modulate small-intestinal immune responses as suggested by the fact that activated CCR9(+) CD8alphabeta(+) lymphocytes selectively localized to the small-intestinal mucosa, and in vivo neutralization of CCL25/TECK reduced the ability of these cells to populate the small-intestinal epithelium. These results demonstrate an important role for chemokines in the localization of T lymphocytes to the small-intestinal mucosa. (Svensson et al., J. Clin. Invest., 2002, 110:1113-21). CCR9+ gut-homing lymphocytes have also been implicated in primary sclerosing cholangitis, a chronic liver disease that is a common complication of inflammatory bowel disease (Eksteen et al., J. Exp. Med., 2004, 200:1511-1517).
CCR9 receptor expression on human eosinophils from peripheral blood and bronchoalveolar lavage fluid after segmental antigen challenge was reported recently (Liu et al, J Allergy Clin Immunol 2003 September; 112(3):556-62). Studies by Singh et al. (Clinical Cancer Research, 2004, 10, 8743-8750) suggest that the expression and activation of CCR9 affect cancer cell migration, invasion, and MMP expression, which together may affect prostate cancer metastasis. In a similar fashion, functional CCR9 has been detected on the surface of small intestinal melanoma (Letsch et al., 2004 J. Invest. Dermatol. 122:685-690).
CCR9 was also found to be selectively expressed on T-ALL CD4+ T cells and moderately expressed on T-CLL CD4+ T cells. CCL25,TECK selectively induced T-ALL CD4+ T cell chemotaxis and adhesion (Qiuping et al., Cancer Res. 2003 Oct. 1; 63(19):6469-77. Annels et al., Blood 2003). A recent study also demonstrates an increase in the expression of CCR9 on peripheral blood gammadelta T cells in individuals having HIV-1 infection (Poles et al., J. Virol. 2003 October; 77(19):10456-67).
Because of the involvement of the CCR9 receptor in a variety of diseases, there is a continuing need for compounds that modulate the binding or function of various chemokines to the CCR9 receptor.